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the addition of chlorine to ably after being freed of'excess chlorine, can be g, UNITED STATES PATENT oFF- c z 4 smnnsls oremo rmazoms v Walter G. Ohristiansen, Glen mo e, N. 1., assignor to E. R. Squibb & S

corporation of New York ,.New York, N. Y., a

No Drawing. Application January 13, 1940,

' Serial No. 313,793

12 Claims. ('01. 260-302) This invention relates to, and has for its object the provision of, an improved method of preparing 2-amino-4-Y- (meta) -thiazoles, wherein Y represents hydrogen, alkyl (preferably lower alkyl) or aryl (preferably phenyl); especially an improved method of: preparing 2 -amino-thiazole. The 2-amino-4-Y-thiazoles are val' ble intermediates for the production of chemot agents.

2-amino-thiazole has been prepared heretofore by reacting a,fl-dichlor-'ethy1 ether with thiourea: u,p-dichlor-ethyl ether, however, is not commercially available, and its production in quantity involves hazardous and/or expensive procedures. 2-amino-thiazole has also been prepared heretofore by .reactingp chloracetal with thiourea, the chloracetal being obtained, for example, from -a,p-dichloro-ethyl acetate.

It has been found that 2-amino-thia zole may be easily and efliciently prepared byreacting an cnfl-dihalo (preferably dichloro) -ethyl acetate directly with thiourea, elimination of the conversion of the halo ester into the halo acetal, and of the separation and isolation of the latter, being obviously of great practical importance. The 41,5- dihalo (preferably dichloro.) -ethyl acetate is erapeutic possibly alkali, the. amino thiazole content varying from as low as 60% to above 90%. While it is possible to use the product in this unrefined form, it is a relatively simple matter to produce products of exceptionally high purity from the reaction products of this invention. This can be done by the organic solvent procedures well known to those skilled in the art,

" 'or still better by distillation (including sublimae 1 readily obtainable by the low-temperature addi-.

tion' of a halogen to vinyl acetate (cf. British Patent 325,115), the latter being an inexpensive, commercially-available compound. It has also been found that the dihalo-ethyl acetate "pre-' pared from vinyl acetate doesnot have to be isolated as such for reaction with thiourea; thus. the entire reaction 7 vinyl acetate, preferproduct (weight 53.3

due in the subliming flask.

tion) under reduced pressure. The following examples are illustrative of the invention:

Example 1 80 g. distilled e,s-dlchloro-ethyl acetate (b; p.-

6267 C./11 mm. or 162 C. at atmospheric pressure) is added dropwise, while stirring, t'oa st lution of 46.4 g. thiourea in 100cc. water heated to 100 C.; and the reactionimixture is maintained at 100 C. for three hours.'. The resulting solution is cooled to 10-15 C., 150 cc. of a concentrated aqueous solution of sodium hydroxide is added, and the product separating from the solution is filtered and dried. The crude g.) may be refined by heating at 150-190? C. in vacuo (-3 'mm. mercur-y or less). the'2-amino-thiazole subliming into the receiver as a white solid melting at 89;5-90.5 C., and .a mixture of sodium chloride remaining as a resi- The yield is 44 g.

d (86.5% of the theoretical).

mixture obtained by reacted directly with thiourea. This is an additional practical advantage, since the dihaloethyl acetates are powerful lachrymators, and it is highly desirablethat the handling of them as intermediates be minimized.

Manifestly, this method of preparing 2-aminothiazole isapplicableto the preparation of. 2- ami'no-4 -Y-tthiazoles generally (Y having the meaning given hereinbefore) thus, a 2-amino-4- Y-thiazole may be prepared by reacting thiourea with an a,p-dihalo-p-Y-ethyl ester of a lower fatty acid, obtainable by the addition of a halogen to the corresponding p-Y-vinyl esterof a- Example 2 80 g. crude oi.p-dichloro-ethyl acetate (obtained by treating vinyl acetate with an excess 'of-chlorine and removing the excess by applying vacuumto the reaction vessel, or by blowing ni-' 'trogen through it) is. reacted with a solution of 46.4 g. thiourea in 100 cc. water in the manner described in Example .1; after heating for three hours at 100 0., 150 cc. ofa concentrated aqueous solution of sodium hydroxide is added; and.

the product which separates from solution is drained on a Buchner funnel and dried., The crude product (weight g.) may be refined as described in Example 1, 43.5 g'. of 2-aminothiazole being obtained as a white solid meltins at 89.5-90.5" 0. (the yield being 84% of the theoretical). Y Y

Example} z-amlno-thlezore is' a,p-dibromoethyl acetate (of. British Patent 325,115). with thiourea in Example 1.

prepared by reacting in the manner described Example 4 2-amino-4-methyl-thiazole is prepared by reacting (2,.B-dlhlOI'O-PIODY1 acetate with thiourea in the manner described in Example 1.

. Example 6 2-amino-4-phenyl-thiazole is prepared by reacting a,p-dibromo-phenethyl acetate with thiourea in the manner described in Example 1.

The invention may be variously otherwise emacid, Y representing a member ofthe group consisting of hydrogen, alkyl, and aryl.

5. The method of preparing Z-a'mIno-thiazole, which comprises reacting thiourea with an apdihalo-ethyl ester of a lower fatty acid.

6. The method of preparing 2-amino-thiazole which comprises reacting thiourea with the crude bodied within the scope of the appended claims.

I claim: a

1. The method of preparing a 2-amlno-4-Y- thiazole, which comprises reacting thiourea with an ap-dihalo-p-Y-ethyl ester of a lower fatty acid, Y representing a member of the group consisting of hydrogen, alkyl, and aryl.

2. The method of preparing a 2-amino-4-Y- thiazole, which comprises reacting thiourea with the crude product obtained by the addition of a halogen to a p-Y-vinyl ester of a lower fatty acid, Y representing a member of the group consisting of hydrogen, alkyl, and aryl.

3. The method of preparing a 2-amino-4-Y- 'thiazole, which comprises reacting thiourea with an a.c-dlchloro-p-Y-ethyl ester of a lower fatty acid, Y representing a member of the group con;- sisting of hydrogen, alkyl, and aryl.

4. The method of preparing a 2-amino-4-Y- thiazole. which comprises reacting thiourea with the crude product obtained by the addition of chlorine to a p-Y-vinyl ester of a lower fatty product obtained by the addition -of halogen to a vinyl ester of a lower fatty acid.

'7. The method of preparing 2-amino-thiazole which comprises reacting thiourea with a,p-di-.

chloro-ethyl acetate.

8. The method of preparing 2-amino-thiazole which comprises reacting thiourea with the crude product obtained by the addition of chlorine to vinyl acetate.

9. The method of preparing a 2-amino-4-Y- thiazole, which comprises heating an aqueous solution of thiourea with an a,fl-diha10-fl-Y- ethyl ester of a lower fatty acid, Y representing a member of the group consisting of hydrogen, alkyl, and aryl.

10. The method of preparing a 2-amino-4-Y- thiazole, which comprises heating an aqueous solution of thiourea with the crude product obtained by the addition of a halogen to a p-Y- vinyl ester of a lower fatty acid, Y representing a member of the group consisting of hydrogen. a1kyl,.andaryl.

11. The method of preparing Z-amino-thiazole which comprises heating an aqueous solution of thiourea with mp-dichloro-ctlwl acetate.

12. The method of preparing 2-amino-thiazole which comprises heating anaqueous solution of thiourea with the crude product obtained by the addition of chlorine to vinyl acetate.

wAL'rER G. cmusmsmz. 

